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Drug Safety 8 (5): 340-349. 1993 0114-5916/ 93/0005-0340/$05.00/0 © Adis International Limited. All rights reserved.

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Minimising the Risks of PUV A Treatment

Marinus CG. van Praag,I,2 Larissa N.L. Tseng, I A. Mieke Mommaas,2 Bart W. Boom2 and Bert Jan Vermeer2

I Department of Dermatology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands 2 Department of Dermatology, University Hospital, Leiden, The Netherlands

Contents

340 Summary 341 1. Short Term Adverse Effects of PUYA Therapy 342 2. Long Term Risks of PUY A Therapy 343 2.1 Chronic Actinic Damage 343 2.2 Dyskeratotic and Precancerous Skin Tumours 343 2.3 Nonmelanoma Skin Cancer 344 2.4 Immunological Alterations 345 2.5 Ophthalmological Effects 345 3. Minimising the Long Term Risks of PUY A Therapy 347 4. Conclusion

Summary Psoralen photochemotherapy (PUY A) is a combination of orally administered psoralen and long wave ultraviolet-A radiation (UY A), and is one of the most effective forms of therapy for psoriasis. The unwanted effects ofPUYA therapy can be divided into short and long term adverse effects. The short term adverse effects include erythema, pruritus, nausea and headache. While short term adverse effects are limited and reversible after discontinuation of treatment, potential long term adverse effects such as chronic actinic skin damage, dyskeratotic and precancerous skin conditions, non melanoma skin cancer, immunological alterations and cataract formation are of greater concern.

Long term risks associated with PUY A therapy can be minimised by several measures. Careful patient selection is mandatory; for example, patients with chronic actinic damage and a history of skin cancer may bear a higher risk for the development of new cancers, and previous arsenic intake and ionising radiation also increase the risk of non melanoma skin cancers. Certain drug combinations make it possible to lower the UY A dose, which is important because of the dosedependent increase in the incidence of SQuamous cell carcinomas in patients treated with PUY A. It has been demonstrated that 200 treatments or a total UYA dose of 1200 J/cm2 seems to be the threshold for development of non melanoma skin cancer. Shielding male genitalia during PUY A treatment is essential because of the increased risk of genital squamous cell carcinomas. Yearly dermatological examination to detect skin cancer at an early stage is highly advisable. Sunscreen use, protective clothing and avoidance of sun exposure reduce the uncontrolled dose of solar UY radiation. Other psoralens with a less carcinogenic potential can be used. UY A-opaque sunglasses during the entire period of increased photosensitivity after psoralen ingestion help avoid cataract formation.

Minimising the Risks of PUV A Treatment 341

Assignment to PUV A ought to be based on the risk-benefit ratio for the individual patient and should be limited to those who can be monitored and controlled by informed, competent and conscientious physicians.

Psoralen photochemotherapy (PUV A) is a combination of orally administered psoralen and long wave ultraviolet-A radiation (UV A) which brings about a therapeutically beneficial result not produced by either the drug or UV A radiation alone. This particular form of therapy is currently used in the treatment of several common and uncommon skin diseases, such as psoriasis, atopic dermatitis, vitiligo, polymorphous light eruption and mycosis fungoides. Psoralens may be applied topically, but systemic administration has been proven to be more practical and easier to control, and has a lower incidence of undesirable adverse effects. Since oral PUV A now represents the most widely used form of photochemotherapy, this article will focus on this type of treatment.

Psoralens can be derived from a number of plants, such as lime, lemon, bergamot, parsley, celery, fig and clove. The use of extracts or parts of plants (Ammi majus) containing natural psoralens and subsequent exposure to sunlight as a treatment for vitiligo dates back to ancient Egyptian, Indian and Chinese healers. A study of the efficacy of psoralens in the treatment of vitiligo in Egypt in the 1940s by EI Mofty (1968) and the subsequent work of Parrish et al. (1974) indicated that this group of compounds could be used to affect epidermal proliferative diseases, such as psoriasis, by inhibition of cellular DNA synthesis which took place following the interaction between psoralen and UV A in the skin. However, a direct disturbance of epidermal cell DNA function is not the only biological effect ofPUVA therapy in psoriasis, since the treatment also affects the immune system in the skin, and may in addition have a systemic effect (Van Praag et al. 1991).

The psoralens used in PUV A therapy are mainly 8-methoxypsoralen (8-MOP), trimethoxypsoralen (TMP), and 5-methoxypsoralen (5-MOP). TMP is a synthetic psoralen, whereas 8-MOP and 5-MOP

are derived from plants. The most widely used derivative in PUVA therapy is 8-MOP, which is given orally in a dose of 0.6 mg/kg. It reaches a maximum concentration in the plasma about I to 2 hours after ingestion. In most individuals it is reasonable to assume that 2 hours after ingestion is the best time for the skin to be exposed to UV A.

8-MOP is metabolised in the liver where it demonstrates a saturable first-pass effect. It has a serum half-life of approximately 1 hour and is rapidly eliminated. The short serum half-life prevents prolonged photosensitivity. The psoralens are extensively metabolised, with only trace amounts being detected in the urine or bile. Urinary and faecal excretion of psoralen metabolites are 74 and 15%, respectively. 80% of the excretion has taken place in 6 to 8 hours and 90% in 12 hours. Following repeated doses of psoralens, there does not appear to be significant accumulation in the body (Gupta & Anderson 1987).

Like any effective treatment, PUV A therapy is associated with certain risks that arise from the toxic properties of 8-MOP, the action of UVA radiation and the molecular-biological effects of UV A on 8-MOP. Most of the known risks of PUV A therapy are UV A dose related, so that the greatest frequency of adverse effects is associated with highexposure doses of the treatments. Unwanted effects of PUV A therapy can be divided into acute (short term) and chronic (long term) adverse effects. There is now considerable clinical experience regarding the short term safety of PUV A, but the risks of potential long term adverse effects are, as yet, not clearly determined. This article primarily focuses on long term adverse effects and discusses several approaches to minimise these risks.

1. Short Term Adverse Effects of PUVA Therapy

Acute adverse effects are related to the patient's inability to tolerate psoralens or overdosing with long wave ultraviolet radiation (UV A). The most

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frequent adverse etTect due to overexposure is erythema (Parrish et aI. 1974). Depending on the dose, it varies from a pink to a severe violaceous erythema with oedema and blistering. Compared with UVB erythema, PUV A-induced erythema appears later, lasts longer and is more intense. It has an onset at 24 hours, peaks at 36 to 72 hours and resolves over the next week, whereas UVB erythema has an onset 2 to 6 hours, peaks at 12 to 24 hours and resolves over 48 hours (Warin 1978).

There is no satisfactory treatment for PUV Ainduced erythema other than cool compresses, emollient lotions and shielding of the atTected area. Topically applied corticosteroids and orally administered indomethacin may be helpful. Overdose phenomena usually arise in areas normally not exposed to natural sunlight. Careful observation of the criteria for dosimetry and the guidelines for treatment can minimise these adverse etTects to an acceptable level and do not interfere with therapy in general (W oltT et al. 1977).

Pruritus is also dose related, and usually manifests as a mild and transient itching. Intense, sometimes torturing pruritus may occur in severely overdosed skin (WoltT & Honigsmann 1981). Pruritus can be treated by oral antihistamines or bland emollients. If pruritus persists, the atTected area should be shielded during therapy or exposure times should be reduced. In a few patients, painful stinging sensations in exposed skin occur towards the end phase of treatment. This is refractory to any treatment but usually disappears spontaneously after about 2 weeks.

Transient nausea is relatively common with 8-MOP used as a photosensitiser (Parrish et al. 1974), but occurs only rarely with 5-MOP (Tanew et al. 1988). Nausea can be minimised by taking the psoralens with food or milk, decreasing the dose of psoralen, splitting the dose so that half the dose is taken 21/2 hours and the rest 2 hours before receiving UV A radiation, or using antiemetics. Only on rare occasions is nausea so severe that discontinuation of PUV A therapy is necessary (Gupta & Anderson 1987).

Very rare short term adverse etTects of PUVA include acne-like eruptions, polymorphous light

Drug Safety 8 (5) 1993

Table I. Long term risks of PUVA therapy

Chronic actinic skin damage (xerosis, wrinkles, freckles)

Dyskeratotic or precancerous skin conditions (actinic

keratosis, PUVA keratosis keratoacanthoma, Bowen's

disease)

Nonmelanoma skin cancer (squamous cell and basal cell carcinoma)

Immunological alterations Ophthalmological effects (cataracts)

eruption-like rashes, transient hypertrichosis of the face and nail changes, such as subungual haemorrhages, onycholysis and pigmentations due to photo toxic reactions in the nail bed (Parrish et al. 1974). These adverse etTects disappear after discontinuation of treatment.

Single case reports have described aggravation of underlying skin diseases including bullous pemphigoid, lupus erythematosus, seborrhoeic dermatitis, acne VUlgaris and herpes simplex (Gupta & Anderson 1987).

2. Long Term Risks 0/ PUVA Therapy

While short term adverse effects of PUV A therapy are limited and reversible after discontinuation of treatment, long term adverse etTects are of greater concern. From in vitro experiments and animal studies, psoralens and UV A are known to have mutagenic (Schenley & Hsie 1981; Swanbeck & Thyresson 1974) and carcinogenic effects (Griffin 1959; Pathak et al. 1959). It is to be expected that these effects are of relevance to humans. Potential long term adverse etTects ofPUVA therapy include chronic actinic damage, dyskeratotic and precancerous skin tumours, nonmelanoma skin cancer, immunological alterations and ophthalmological effects (table I). It is assumed that these adverse etTects depend on the total cumulative UVA dose received over a prolonged period of time and may be fully identified only after an extended period of latency (WoltT & Honigsmann 1981).

Analysis oflaboratory data in several large scale studies has not revealed significant abnormal find-

Minimising the Risks of PUY A Treatment

ings in patients receiving long term PUY A therapy (Henseler et al. 1981; Melski et al. 1977). Since psoralens can produce liver damage in laboratory animals when given in excessive doses (Wolff 1990), concern has been expressed in the past about possible hepatotoxic effects in humans. However, serial laboratory examinations performed over a period of several years have not revealed any substantial evidence of impairment of hepatic function (Wolff & H6nigsmann 1981). A slight increase in blood urea nitrogen (BUN) and creatinine has been documented in one series (Wolff 1990), but was considered insignificant; there has been no evidence suggesting impairment of renal function in large scale studies (Henseler et al. 1981; Melski et al. 1977). An increased incidence of antinuclear antibodies in PUV A-treated patients was reported by Bjellerup et al. (1979), but several other studies have not shown such relationships (Gschnait et al. 1980; Levin et a1.1982; Stern et al. 1979a).

2.1 Chronic Actinic Damage

Repeated phototoxic injury to the skin can be expected to result in cumulative actinic damage regardless of whether it is induced by sunlight, artificial UV radiation or PUV A. Although the precise action spectrum of actinic damage has not been determined, epidermal changes are attributed to UVB and dermal changes to UV A because the latter penetrates more deeply into the skin. Long term exposure to PUV A may thus produce changes in the skin that resemble premature aging induced by sunlight (Langner et al. 1977). Early in the course of therapy the skin becomes dry and wrinkled; these changes are fully reversible after cessation of therapy. However, with long term treatment changes become more marked, with the appearance of telangiectasia and disturbance of melanisation in the form of freckling (Swart et al. 1984) and macules of hypopigmentation. This pigmentary phenomenon, for which the term 'PUV Ainduced mottling' has been coined, is observed in a minority of patients and is mainly, but not invariably, restricted to areas of overdosage (Gschnait et al. 1980).

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Table II. Characteristics of the various skin types

Skin Characteristics

type

Always burn, never tan II Usually burn, tan less than average (with difficulty) III Sometimes mild burn, tan about average

IV Rarely burn, tan more than average (with ease) V Moderately pigmented skin VI Heavily pigmented

As with sunlight, the development of premature aging of the skin from PUV A treatment is closely related to skin type (table II). Thus, patients with skin types I and II show most marked changes, while little or no change is seen in skin types V and VI. The dose ofPUVA is also important; when PUV A treatment was introduced, very high doses tended to be used to achieve complete clearance, and aging appeared earlier than with the present low dose regimens (Morison 1991).

2.2 Dyskeratotic and Precancerous Skin Tumours

Development of actinic keratoses is the most common precancerous condition that occurs during PUV A treatment (Stuttgen 1982). PUV A therapy may also be associated with Bowen's disease and keratoacanthomas (Hofmann et a1.1979; H6nigsmann et al. 1980; Sina & Adrian 1983). Recently, we introduced the term 'PUV A keratosis', a newly described hyperkeratotic lesion, observed in PUV A-treated patients (Bruynzeel et al. 1991). It appeared that 'PUV A keratoses' could be regarded as predictive lesions for an increased risk for non melanoma skin cancer, especially squamous cell carcinomas (Van Praag et al. 1993).

2.3 Nonmelanoma Skin Cancer

The combination of psoralen and UV A radiation is mutagenic in a variety of systems, including mammalian cell lines (Schenley & Hsie 1981; Swan beck & Thyresson 1974). PUV A is also carcinogenic in mice and causes the development of

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squamous cell carcinomas in the skin (Griffin 1959; Pathak et al. 1959). Therefore, it is not surprising that PUV A treatment is associated with non melanoma skin cancer in humans.

This adverse effect appeared in a 16-centre cooperative study in the US (Stern et al. 1979b). The increased risk of nonmelanoma skin cancer was particularly evident in patients with a previous history of ionising radiation therapy or previous cutaneous carcinoma. The risk was apparent in the second year after initiation of PUV A and was sustained (dose-dependently) after 5 and 10 years (Stern & Lange 1988). The incidence of squamous cell carcinoma was significantly higher than that expected in the general population and was particularly high in those areas of the skin not usually exposed to the sun (Forman et al. 1989; Stern et al. 1979b). Other factors that influence the risk of developing squamous cell carcinomas include the intensity of treatment and the skin type of the patient (table II). A large number of treatments over a short period of time is more carcinogenic than less intensive treatment, and patients with skin types II and III account for much of the increased risk (Lindelof et al. 1991).

The incidence of basal cell carcinoma was also significantly elevated over that in the general population. The increase in basal cell carcinoma may be ascribed to a tumour-promoting effect of PUV A and/or a propensity of patients with psoriasis to develop more basal cell carcinomas than nonpsoriatic individuals (Stern et al. 1985).

In contrast with the American studies, most large scale European studies have not found an increased risk for squamous cell carcinomas in patients treated with PUV A long term unless they belong to the risk groups mentioned above (Eskelinen et al. 1985; Henseler et al. 1987; Tanew et al. 1986). In Europe, a PUV A schedule is used which provides for fewer but higher phototoxic PUV A doses than the schedule used in the US. This more aggressive treatment schedule is less carcinogenic in the murine model (Gibbs et al. 1986) and may account for the lower incidence of squamous cell carcinomas in these series. Recently, however, it has been demonstrated that the European PUV A


regimen also causes an excess of squamous cell carcinomas (Bruynzeel et al. 1991; Lindelof et al. 1991).

The most alarming recent report from the US appeared in 1990, when Stern et al. described a strongly dose-dependent increase in the risk of genital squamous cell carcinomas in PUV A-treated men. A lower incidence of genital tumours in males was reported by Lindelof et al. (1991) in a Swedish study.

The gravest concern about oncogenic risks of PUV A therapy relates to the induction of malignant melanoma. Although morphological data in some studies have indicated irreversible structural changes in melanocytes, malignant melanoma has been observed in only a few PUV A-treated patients (Frenk 1983; Gupta et al. 1988). So far, there is no evidence to support an increased frequency of melanoma in patients exposed to PUV A for prolonged periods of time (Gupta et al. 1988).

2.4 Immunological Alterations

PUV A has been shown to alter immune responses. In animal systems as well as in human studies, it has been found that PUV A causes a variety of changes in the function of lymphocytes in a dose-dependent fashion (Morison et al. 198Ia), possibly as a result of impaired interleukin-2 production (Okamoto et al. 1987). It also diminishes the induction of allergic contact dermatitis and delayed hypersensitivity (Horio & Okamoto 1982; Morison et al. 198Ib). Full-thickness graft survival was prolonged in animals after exposure of donors' and recipients' sites (Morison et al. 1980). One important factor for these phenomena may be an impairment of Langerhans cell function, represented by the reduction of the epidermal allostimulatory capacity in the mixed epidermal cell-lymphocyte reaction (Van Praag et al. 1991). Several studies reported a reduced number of Langerhans cells in PUV A-treated experimental animals, human volunteersand patients with psoriasis, using either A TPase or major histocompatibility complex (MHC) class II molecules as identification markers (Friedmann 1981; Stingl et al. 1986). However, on the


ultrastructural level a depletion of Langerhans cells or the loss of MHC class II molecules could not be demonstrated (Mommaas, personal communication).

The reversibility and clinical significance of these alterations are unknown, but they suggest that PUV A may suppress immunological surveillance not only locally in the skin but also systemically (Van Praag et al. 1991). The therapeutic success of PUV A in disorders such as vitiligo, atopic eczema, alopecia areata, lichen planus and some photodermatoses may be based on such immunosuppression. Impairment of immunological surveillance has been speculated to play an important role in the development of skin carcinomas in that PUV A may act as a pseudopromotor by blocking the recognition of new tumour antigens by Langerhans cells in the skin, which may allow the expression of potentially malignant foci (Strauss et al. 1980).

Besides an increased incidence of recurrent herpes simplex, there is no evidence for an increased risk for viral, bacterial or fungal infections in PUV A-treated patients (Wolff 1990).

2.5 Ophthalmological Effects

Evidence for the potential ocular toxIcIty of PUV A therapy is mainly based on experimental studies. UV A is largely transmitted by the human cornea and absorbed by the ocular lens. Orally administered 8-MOP diffuses in many tissues, including the ocular lens. In the absence of UV A, 8-MOP diffuses out of the lens in approximately 24 hours without causing damage (Lerman 1982). However, if the lens is irradiated with UV A within this period, 8-MOP can be excited and is able to bind irreversibly with nucleic acids, primarily the thymine bases in DNA molecules, as well as with lens proteins, especially the aromatic amino acid tryptophan (Lerman 1982). Since the lens is a completely encapsulated organ and almost never sheds its cells, the photobound 8-MOP can be retained in the lens tissue and accumulate during PUV A therapy. The protein-bound 8-MOP probably acts as a photosensitiser and can initiate additional protein damage via the singlet oxygen pathway. All of

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this can result in gradual loss of transparency of the lens with cumulative damage, leading to cataract formation (Lerman 1980).

So far, there is no convincing evidence that psoralen-induced cataracts occur in patients subjected to long term PUV A therapy. As long as there is uncertainty about the actual risk of eye toxicity, it is recommended that adequate protective measures are taken.

3. Minimising the Long Term Risks of PUVA Therapy

The major concern relates to long term treatment of psoriasis since this condition represents by far the most common indication for PUV A. As long as the risks of long term use are not clearly assessed, careful patient selection appears to be mandatory.

Relative contraindications include conditions potentially aggravated by PUV A, such as cataracts or aphakia, and severe cardiovascular, hepatic and renal disease. Immunosuppressed patients should probably not receive PUV A because the treatment may add to the already existing immunosuppression. PUV A should preferably be limited to older patients. It is not advisable for patients under the age of 18 years as these are at greater risk for long term adverse effects.

Absolute contraindications include: a history of arsenic intake, and ionising radiation or skin cancers since these increase the risk of developing cutaneous malignancies; a history of photosensitivity diseases such as lupus erythematosus, xeroderma pigmentosum, albinism and porphyrias; and idiosyncratic or allergic reactions to psoralens. PUV A should not be used during lactation or pregnancy, and female patients should be advised to use contraceptive measures while on PUV A (Gupta & Anderson 1987). This precaution is only for reasons of safety as there is no evidence that either 8-MOP alone or PUVA are teratogenic (Wolff & Hbnigsmann 1981). Attention must be paid to potential drug interactions with other photosensitising drugs that could result in an increased risk of PUV A phototoxicity. Representative examples of the

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Table III. Summary of approaches to the minimisation of long

term risks associated with PUVA therapy

• Avoid long term maintenance treatment as much as possible; combination therapy can reduce total exposure

• Shield areas that are prone to skin cancer (face, male genitalia)

• Yearly dermatological examination • Use of sunscreens and protective clothing • Trimethoxypsoralen (TMP) may be less carcinogenic than

8-methoxypsoralen (8-MOP)

major classes of photosensitising drugs are nalidixic acid, p-aminobenzoic acid derivatives, phenothiazines, sulphonamides, sulphonylureas, tetracyclines, thiazides and related sulphonamide diuretics. Most of these drugs have an action spectrum in the UV A range. An extensive list of photosensitising drugs can be found in a review article by Abramowicz (1986).

It is important to be aware of the fact that patients with skin types II and III may have the highest risk of developing non melanoma skin cancer (Lindeloff et al. 1991). Patients with skin type I (always burn, never tan) should be treated conservatively (with lower incremental doses ofUVA) while those with type IV (always tan, never burn) have an inborn shield against UVA because of their ability to pigment. These 'protective effects' are diminished in patients with skin types II and III, who might receive undesirable high doses of UV A.

Apart from conscientious patient selection, there are several accepted approaches to minimise the long term risks associated with PUV A therapy (table III).

First, long term maintenance treatment should be avoided as much as possible. It has been demonstrated that 200 treatments or a total UV A dose of 1200 J/cm2 seems to represent a threshold for development of non melanoma skin cancer, and strategies which reduce the intensity and the total dose of PUV A should therefore decrease that risk (Lindeloff et al. 1991). Educating patients to accept less than 100% clearance is an important element in this approach. The use of combination therapy also helps to reduce total exposure. One method is the combination of oral treatment and limited 10-


cal treatment with 8-MOP (Stuttgen 1982). This means using the same UV A doses but with higher concentrations of 8-MOP at the lower epidermis and upper corium. However, this produces a higher sensitivity to UV A radiation, which makes this combination therapy difficult to perform. The combination of PUV A therapy and locally applied corticosteroids can be helpful in cases of resistant psoriatic lesions. It is widely accepted that the greatest reduction in the sum of 8-MOP and UV A radiation can be achieved by oral administration of retinoids. Retinoids increase the efficacy of PUV A therapy and are especially recommended in cases where PUV A therapy has to be intensified, for instance in patients who show slow improvement (Morison 1985). Moreover, retinoids have a preventive effect against the development of squamous cell carcinomas (Hong et al. 1990). However, it must be kept in mind that the combination of retinoids and PUV A therapy compared with PUV A alone has the disadvantage of increased occurrence of adverse effects and teratogenicity when female patients are treated. The combination of PUV A therapy and tar treatment is not advisable, because tar is a known carcinogen (Stern 1990).

Secondly, it is prudent to shield areas that are prone to skin cancer. The face should be covered during PUV A treatment unless it is affected by disease, since the face is predisposed to develop suninduced skin cancer. Male genitalia should be shielded during PUVA treatment because of the increased risk of squamous cell carcinomas in that area (Stern 1990).

Thirdly, yearly dermatological examination of all PUV A-treated patients is recommended because of the dose-dependent risk of developing nonmelanoma skin cancer. From 1975, all patients who have received more than 20 J/cm2 are screened yearly at our Department of Dermatology (University Hospital, Leiden) to detect skin cancer at an early stage. In our study, we found that the overall risk of developing squamous cell carcinomas was 12 times higher than expected in the general population; for basal cell carcinomas there was a 5-fold increase in risk (Bruynzeel et al. 1991). Although cutaneous malignancies in PUV A-treated


patients are not biologically aggressive we consider this approach as strongly advisable. In particular, a careful follow-up of patients with psoriasis and 'PUV A keratoses' is recommended, since the presence of these keratoses is associated with an increased risk of nonmelanoma skin cancer; therefore, cessation of PUV A treatment should be considered (Van Praag et al. 1993).

Fourthly, it is important that PUVA patients apply sunscreens that absorb both short-wave (UVB) and long-wave (UV A) UV radiation, particularly following daytime PUV A therapy. They should wear protective clothing (long sleeves, high collars, hats, etc.) after psoralen ingestion on the day of treatment. In addition, repeated daily sunscreen use (except before PUVA treatment) is important in order to reduce the risk of phototoxic reactions occurring from sunlight or from filtered sunlight through window glass (UV A passes through window glass). In addition, when local phototoxic reactions occur during PUV A therapy, local sunscreen application may be used to reduce UV A radiation during subsequent PUV A therapy.

Fifthly, use of TMP instead of 8-MOP should be taken into consideration because this compound may be less carcinogenic. Recently, Lindelof et al. (1991) reported that PUV A-treated patients receiving TMP showed no overall increased risk of nonmelanoma skin cancer in contrast with patients receiving 8-MOP.

The potential ocular complications of PUV A therapy are extremely important, both because of the associated morbidity and because these complications are preventable. To avoid cataract formation, it is necessary that appropriate UV Aopaque sunglasses are worn during the entire period of increased photosensitivity after psoralen ingestion. Shielding the eyes for at least 8 hours after 8-MOP ingestion is recommended (Morison & Strickland 1983). It has been suggested that any patient on PUV A therapy should obtain ophthalmological examination before initiating treatment, at 6 months, at I year after the start of treatment and yearly thereafter (Farber et al. 1982). At present, the indications are that if adequate eye protection is provided, PUV A will not induce ocular

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tOXICIty in humans (Wolff 1990). Therefore, we consider regular ophthalmological examinations to be unnecessary.

A lot of different sunglasses are available, mainly coloured ones, which differ in their UV A absorption capacity. Therefore, selection of suitable sunglasses is very important. Recently, Deleu and Roelandts (1990) evaluated experimental uncoloured sunglasses and compared them with commercially available coloured sunglasses. Several coloured sunglasses gave excellent protection over the entire UV A range as well as the experimental uncoloured sunglasses. In contrast with uncoloured sunglasses, dark sunglasses can be very inconvenient, unpractical and cosmetically unacceptable, which decreases compliance. Therefore, uncoloured sunglasses can be regarded as the first choice for adequate eye protection during PUV A therapy, and the industry should be encouraged to manufacture them.

4. Conclusion

PUV A therapy, although associated with various risks, is a fascinating treatment concept. Its exciting future must include the development of new UV A-sensitisers and different wavelengths in order to minimise the risks. After 18 years of experience with PUV A for the treatment of psoriasis, it has become evident that this therapy offers patients the chance to resume a normal life. However, in view of the potential risks, patients should be carefully selected and the treatment limited to those who can be monitored and controlled by informed, competent and conscientious physicians.

Acknowledgements

We would like to thank Dr H.E. Menke (Dermatologist, Sint Franciscus Gasthuis, Rotterdam) for critical reading of the manuscript. Part of this work was supported by grant 28-1739 of the Praeventie Fonds, The Netherlands.

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Correspondence and reprints: Dr M.C.G. van Praag, Department

of Dermatology, University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

9th International Symposium on

Pharmacology of Thermoregulation Date: 8-12 August 1994

Venue: Giessen, Germany Preliminary registrations due 31 December 1992

For further information, please contact: Prof. Dr Eugen Zeisberger Physiologisches Institut

Klinikwn der JLU Giessen Aulweg 129

06300 Giessen Federal Republic of Germany